This invention pertains to a novel polypeptide having mammalian growth factor activity and to methods for using it.
A variety of diffusible factors which stimulate the growth of cells in a hormone-like manner are generally called "growth factors". Growth factors are often present in serum and have also been isolated from a variety of organs. They are protein molecules (or groups of such molecules) and in all known cases they interact with specific cell surface receptors to promote cellular growth and/or differentiation. Growth factors vary in their tissue specificity, i.e. some interact only with specific cell types, while others are active on a wider cell type range.
Among the best known groups of mammalian growth factors are: (1) platelet derived growth factor (PDGF), released from platelets; (2) epidermal growth factor (EGF); (3) hematopoietic growth factors (including interleukins 1, 2, and 3), required for growth and differentiation of lymphocytes, and colony stimulating factors (CSF), promoting growth and differentiation of hematopoietic stem cells; (4) angiogenic (literally "blood-vessel-forming") growth factors, such as the fibroblast growth factors (FGF) believed to promote growth and organization of endothelial cells into new blood vessels; (5) miscellaneous growth factors released by tumor cells.
Two well-characterized angiogenic factors are basic and acidic fibroblast growth factors (FGF), believed to be most important in Vivo for endothelial cell growth. However, neither basic FGF nor acidic FGF has proven useful as pharmaceutical agents for promotion of wound healing. Several factors may contribute to the unsuitability of basic FGF and acidic FGF as pharmaceutical agents. Neither factor is sufficiently stable for effective pharmaceutical formulation. Basic FGF demonstrates restricted interaction with FGF receptors in vitro, and thus cannot be expected to interact with all FGF receptors in vivo. Finally, basic FGF and acidic FGF have thus far proven ineffective in animal models.
Co-pending U.S. patent application Ser. No. 07/806,791 filed Dec. 6, 1991 discloses an angiogenic mammalian growth factor isolated from Kaposi's Sarcoma cells and having substantial homology to each of acidic and basic fibroblast growth factor in a single polypeptide. The growth factor protein comprises 176 amino acid residues and is a mature (secreted) glycoprotein. This growth factor has variously been called K-FGF or FGF-4, and it has shown promising results as a wound healing agent in preclinical studies in an ischemic rabbit ear model. In such a model, K-FGF promoted wound healing better than basic or acidic FGF.
Growth factors are believed to promote wound healing. For example, EGF present in saliva is believed to accelerate wound healing in mice. Schultz G.S et al. (Science 232:350-352, 1986) report that transforming growth factor (TGF)-alpha and vaccinia virus growth factor (VGF), both of which are substantially homologous to EGF, accelerated epidermal wound healing in pigs when topically applied to second degree burns and were significantly more active than EGF.
Of the above-mentioned growth factors, the angiogenic growth factors would be particularly useful as wound healing agents because of their ability to promote the formation and growth of new blood vessels.